Intro to Neuromuscular blocking agents · Antimuscarinic agents •These agents 1) competitively block muscarinic receptors . 2)inhibit muscarinic functions. •they are useful in

Intro to Neuromuscular blocking agents

Done by: Ahmad Al-Masri

Quick Cholinergic review

• acetylcholine(ACH) is neurotransmitter of the parasympathetic nervous system.

• ACH is synthesized in the cholinergic neurons from choline and acetyl CoA then stored in synaptic vesicles then it will be release into synaptic gap to bind post synaptic receptors and lead to biological response

- 2 types of Cholinergic receptors:

1) Muscarinic Receptor

2) Nicotinic Receptor

Let’s talk shortly about each separately:

Muscarinic Receptor

•Muscarinic receptors action related to postganglionic parasympathetic (found on effector organ that innervated by parasympathetic).

•Muscarinic Receptor subdivided to:

- M1 receptor found in CNS & GI Glands (mainly there activation lead to ↑HCL in

stomach).

- M2 receptor found in Heart.

- M3 receptor found in Smooth Muscle all over the body.

** all glands of the body are M3 except GI gland M1

- M4,5 receptor found in CNS

•In general stimulation of muscarinic receptors have 3 main effect: 1) Decrease Heart rate 2) Increase Secretion 3) Smooth muscle contraction

•So far, it’s clear that when there is stimulation in

M1 → Increase in HCL secretion.

M2 → Decrease Heart rate But when it comes to M3 it have more than one effect since it’s located in SM all over the body.

Target Response

Eye (sphincter) Contraction Miosis

Lungs (Bronchioles)

(Glands)

Contraction bronchospasm

↑ Secretion

GIT (Stomach)

(Intestine)

↑ Motility

↑ contraction Diarrhea

Bladder 1)contraction of bladder muscle

2)relaxation of the sphincter urinary incontinence

Sphincters Relaxation (except the lower esophageal sphincter contraction)

Glands ↑ Secretion (↑ sweat, salivation, lacrimation)

Blood Vessels Dilation ↓BP

** Muscarinic receptors agonist & antagonist are all Non-selective (so when we give

agonist or antagonist we

suspect effects in all the 3 types)

Nicotinic Receptor

• Nicotinic Receptor subdivided to 2 types:

1) NN which found in → Adrenal gland & Autonomic Ganglia Note: we don’t want to mess with this type cuz it will lead to unspecific & undesirable effects.

2) NM which found in → NMJ (neuromuscular junction) that mean it’s stimulation affect Skeletal Muscles.

• Skeletal muscle relaxation can be produced by:

1. Deep inhalational anesthesia

2. Regional nerve block

3. Neuromuscular blocking agents a.k.a (muscle relaxants)

Physiology of Neuromuscular Transmission

As a nerve’s action potential depolarizes its terminal influx of calcium ions into the nerve cytoplasm fuse of storage vesicles to terminal plasma membrane and release [ACh] diffuse across the synaptic cleft to bind with nicotinic cholinergic receptors on a specialized portion of the muscle membrane, the motor end-plate. Each neuromuscular junction contains approximately 5 million of these receptors, but activation of only about 500,000 receptors is required for normal muscle contraction

Anticholinergic drugs (Cholinergic blockers)

• anticholinergic drugs include:

1. Antimuscarinic agents ( atropine, ipratropium, scopolamine)

2. Neuromuscular blockers (act on Nicotinic receptors in Somatic )

3. Ganglionic blockers (act on Nicotinic receptor in ANS)

Antimuscarinic agents

• These agents 1) competitively block muscarinic receptors . 2)inhibit muscarinic functions. • they are useful in different clinical situations, they have

no actions on skeletal neuromuscular junctions or autonomic ganglia because they do not block nicotinic receptors.

• extent of Anticholinergic drugs effect depends on the degree of baseline vagal tone

Effect of antimuscarinic agents on the different organ systems:

• Cardiovascular: - Blockade of muscarinic receptors in the SA node produces tachycardia

- Transient slowing of heart rate in response to smaller intravenous doses of atropine (<0.4 mg)

- Large doses of anticholinergic agents can produce dilation of cutaneous blood vessels (atropine flush).

• Respiratory: - inhibit respiratory tract secretions, valuable property during airway endoscopic or surgical procedures.

- Relaxation of the bronchial smooth musculature reduces airway resistance and increases anatomic dead space. (COPD & asthma)?

• CNS:

- can cause a spectrum ranging from stimulation(excitation,

restlessness, or Hallucinations) to depression (sedation and amnesia),

depending on drug choice and dosage.

- Cerebral depression, are prominent after scopolamine.

• GI:

- ↓Salivary secretions are. Gastric secretions are also decreased, but larger doses are necessary.

- ↓intestinal motility and peristalsis prolong gastric emptying time.

- ↓ Lower esophageal sphincter pressure.

Overall, the anticholinergic drugs do not prevent aspiration pneumonia.

• Eye: - Topically 1) Mydriasis 2) cycloplegia (an inability to

accommodate to near vision)

- Systemically acute angle-closure glaucoma (rarely)

• Genitourinary: - urinary retention

• Thermoregulation: Inhibition of sweat glands may lead to a rise in body temperature (atropine fever).

ATROPINE • is a tertiary amine (can rapidly cross the BBB) • Dosage: atropine is administered IV or IM in a range of 0.01 to 0.02 mg/kg, up to the usual adult dose of 0.4 to 0.6 mg. • most efficacious anticholinergic for treating

bradyarrhythmias • Patients with CAD may not tolerate the increased

myocardial oxygen demand and decreased oxygen supply

• derivative of atropine, ipratropium bromide, is available in a metered-dose inhaler for the treatment of bronchospasm (limits systemic absorption)

• CNS effects of atropine are minimal after the usual doses.

• associated with mild postoperative memory deficits, and toxic doses are usually associated with excitatory reactions

• should be used cautiously in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction

• IV atropine is used in the treatment of organophosphate pesticide & nerve gas poisoning

SCOPOLAMINE • tertiary amine

• more potent antisialagogue (decrease production of saliva) than atropine and causes greater CNS effects

• Clinical dosages usually result in drowsiness & amnesia, although restlessness, dizziness, and delirium are possible.

• The lipid solubility allows transdermal absorption, and transdermal scopolamine (1 mg patch) has been used to prevent postoperative nausea and vomiting

• Because of its pronounced mydriatic effects, scopolamine is best avoided in patients with closed-angle glaucoma

GLYCOPYRROLATE • synthetic product that differs from atropine in

being a quaternary amine

• dose of glycopyrrolate is one-half that of atropine.

• Due quaternary structure, cannot cross the BBB and is almost devoid of CNSand ophthalmic activity.

• Potent inhibition of salivary gland and respiratory tract secretions is the primary rationale for using it.

• Heart rate usually increases after IV—but not IM.

• Glycopyrrolate has a longer duration of action than atropine (2–4 h versus 30 min after intravenous administration).

• Any Questions so far?!